Blood includes erythrocytes, leukocytes and platelets as cell components. Among them, the leukocytes are classified into five categories: granulocytes (neutrophil, eosinophil and basophil), lymphocytes and monocytes. The neutrophils are the greatest number of cell types in human, and are well known to function on the front line of biological defense against bacterial infection, histological damage, and the like. The neutrophils are activated by bacterial cell components (e.g. lipopolysaccharide: LPS), bacteria-derived peptide, complement C5a, IL-8, and the like. The neutrophil is one of main ingredients of granulocytes in leucocytes, and when a foreign substance like bacteria enters a living body, the neutrophil migrates to its site and phagocytizes a foreign substance such as bacteria to generate active oxygen. Furthermore, the neutrophil plays an important role in release of bactericidal proteins such as lysozyme and defensin (degranulation) and elimination of foreign substances by actions of the proteins as well as various acidic hydrolase, or the like. However, if this active oxygen and the bactericidal proteins are excessively released outside the cells, they cause tissue damages, and optionally worsen an acute inflammation caused by entrance of foreign substances. Furthermore, in cases of particular diseases such as acute pulmonary disorder, acute respiratory distress syndrome and other neutrophil-related inflammations, this action of the neutrophil is known to have adverse effects on diseases.
Neutrophil elastase is a neutral protease having a molecular weight of about 30,000 and present in azurophil granule (lysosome). In a physiological state, in the neutrophil, the neutrophil elastase digests and degrades a phagocytized bacterium and foreign substance, and on the outside of the neutrophil, degrades elastin, collagen (types III and IV), fibronectin, immunoglobulin, blood coagulation factor XIII, etc. to regulate tissue biosynthesis. When the neutrophil elastase is excessively released and inhibitors such as α1-AT (α1-antitrypsin) are deficient, it may degrade even biological constituents and cause its own tissue damage. In inflammation, the neutrophil infiltrates into an inflammatory lesion, but conversely there is an aspect in which inflammation is caused by a substance produced by leukocyte like elastase. Recently, particularly in clinical sites, the kinetics of the neutrophil elastase and various diseases have attracted attentions. The neutrophil elastase has potent and broad degradation ability for proteins, and since it degrades particularly collagen, elastin, proteoglycan, etc. which are extracellular matrix components, it had been considered as one of factors of histological damages. Thus, medicines focusing to inhibitory effects of the neutrophil elastase are being developed. For example, there is a report that an H2 receptor antagonist, ranitidine hydrochloride (Name of drug: Zantac) decreases an intracellular Ca2+ concentration of the neutrophil and reduces release of the neutrophil elastase. In addition, sivelestat sodium (Name of drug: Elaspol) is a specific inhibitor for elastase released from the neutrophil out of the cell, and also a therapeutic agent which has a license to be applied to respiratory distress syndrome and acute pulmonary disorder in Japan. These drugs are not essentially drugs which inhibit activation of the neutrophil, but work on only one factor released by the activated neutrophil to inhibit its enzyme activity, and thus its anti-inflammatory action is expected.
Although there is a report about a substance which acts on a factor released an activated neutrophil and inhibits its activity as mentioned above, an inhibitory mechanism of the neutrophil is largely unknown. Particularly, for preventing runaway activation of the neutrophil in the circulation, the neutrophil should be kept in an inactive state. However, there has been no report about a factor capable of maintaining/regulating the neutrophil in an inactive state.
HRG (Histidine-rich glycoprotein) is a plasma protein with a molecular weight of about 80 kDa which was identified by Heimburger et al. in 1972. HRG is a high histidine-containing protein made up of a total of 507 amino acids in which 66 histidines are contained, and is mainly synthesized in a liver and contained in human plasma at a concentration as extremely high as about 100-150 μg/ml. HRG is known to be involved in regulation of a coagulation fibrinolysis system and control of angiogenesis (Blood, Vol. 117, No. 7, 2093-2101 (2011)). Furthermore, a method for inhibiting angiogenesis by administration of a HRG polypeptide, and a pharmaceutical composition and a product which comprising the HRG polypeptide, an antibody and receptor binding to the HRG polypeptide, a HRG-deficient plasma and polynucleotide, a HRG polypeptide-coding vector and a host cell are disclosed (JP 2004-527242 A). Additionally, in relation to the field of angiogenesis, there is a disclosure relating to the use of a substantially-pure continuous polypeptide with an anti-angiogenesis activity containing a sub-fragment derived from a central area of the HRG (JP 2007-528710 A).
However, there has been no report about effects of the HRG on control of the neutrophil.
Traditionally, the systemic response to infection has been termed sepsis, and it is considered an increasingly common cause of morbidity and mortality, especially in the elderly. Immunocompromised ad critically ill patients. However, a systemic response can occur even in the absence of an infection, in association with several clinical conditions. Non-infectious pathologic causes may include pancreatitis, ischemia, multiple trauma and tissue injuries, hemorrhagic shock, immune-mediated organ injury, and the administration of inflammatory mediators, such as cytokines, for example the tumor necrosis factor. The systemic response may include more than one of the following clinical manifestations: (1) a body temperature greater than 38° C. or less than 36° C.; (2) a heart rate greater than 90 beats per minute; tachypnea, manifested by a respiratory rate greater than 20 breaths per minute, or hyperventilation, as indicated by an arterial carbon dioxide tension (PaCO2) of less than 32 mm Hg; and an abnormal count of white blood cells, such as a count greater than 12,000 μl or less than 4,000 μl.
In 1992, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) proposed the phrase “systemic inflammatory response syndrome” (SIRS), to describe the inflammatory process independent of its cause. The ACCP and the SCCM further classified SIRS into sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). When SIRS is the result of a confirmed infection, it is termed “sepsis.” Severe sepsis is defined as sepsis associated with organ dysfunction, abnormal hypo-perfusion, or sepsis-induced hypotension. Septic shock is a subset of severe sepsis, and is defined as sepsis-induced hypotension, which persists despite adequate fluid resuscitation, along with the presence of hypo-perfusion abnormalities or organ dysfunction. MODS is a pattern of multiple and progressive symptoms and signs that are pathogenetically related. The idea behind the classification of SIRS was to identify the pathogenic mechanisms involved in the systemic inflammatory response.
Infection is defined as “a microbial phenomenon characterized by an inflammatory response to the microorganisms or the invasion of normally sterile tissue by those organisms.” Bacteremia, a condition characterized by the presence of bacteria within the bloodstream, does not always lead to SIRS or sepsis. Sepsis-induced hypotension is defined as “the presence of a systolic blood pressure of less than 90 mm Hg or a reduction of more than 40 mm Hg from baseline in the absence of other causes of hypotension.” Patients meet the criteria for septic shock if they have persistent hypotension and perfusion abnormalities despite adequate fluid resuscitation.
Possible complications may include respiratory failure, acute respiratory distress syndrome (ARDS), and nosocomial pneumonia, renal failure, gastrointestinal (GI) bleeding and stress gastritis, anemia, deep vein thrombosis (DVT), intravenous catheter-related bacteremia, electrolyte abnormalities, hyperglycemia and disseminated intravascular coagulation (DIC). SIRS is considered by many as a self-defense mechanism, where inflammation is the body's response to insults from chemical, traumatic or infectious stimuli. Trauma, inflammation, or infection leads to the activation in SIRS of an inflammatory cascade with increased systemic expression of a first pro-inflammatory response, and a later anti-inflammatory response. When SIRS is mediated by an infectious insult, the inflammatory cascade is often initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells produce cytokines. The release of tissue necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) leads to cleavage of the nuclear factor-kB (NF-kB) inhibitor, which in turn initiates the production of mRNA, with consequent production of more pro-inflammatory cytokines, such as IL-6, IL-8, and interferon gamma. The release of TNF-α and IL-1 produces fever and the release of stress hormones, such as norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system. Release of TNF-α is greater in inflammation than in trauma. IL-6, stimulates the release of acute-phase reactants such as C-reactive protein (CRP) and pro-calcitonin.
Pro-inflammatory interleukins may function directly on tissue or act through secondary mediators to activate the coagulation cascade, the complement cascade and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes. IL-1 and TNF-α also directly affect endothelial surfaces, leading to the expression of tissue factor, which in turn initiates the production of thrombin and the process of coagulation. Fibrinolysis is impaired by IL-1 and TNF-α via production of plasminogen activator inhibitor-1. Pro-inflammatory cytokines also disrupt the naturally occurring anti-inflammatory mediators anti-thrombin and activated protein-C (APC). If untreated, the coagulation cascade leads to complications, including microvascular thrombosis and organ dysfunction.
To counteract the acute inflammatory response, the body activates the counter-inflammatory response syndrome (CARS). IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF-α, IL-1, IL-6, and IL-8. The acute phase response also produces antagonists to TNF-α and IL-1 receptors, which either bind and inactivate the cytokine, a or block the receptors. Comorbidities and other factors can influence a patient's ability to respond appropriately. The balance of SIRS and CARS helps determine a patient's outcome after an insult.
Infectious causes of SIRS include, but are not limited to, bacterial sepsis, burn wound infections, candidiasis, cellulitis, cholecystitis, community-acquired pneumonia, diabetic foot infection, erysipelas, infective endocarditis, influenza, intra-abdominal infections, such as diverticulitis and appendicitis, gas gangrene, meningitis, nosocomial pneumonia, pseudomembranous colitis, pyelonephritis, septic arthritis, toxic shock syndrome, and urinary tract infections.
Noninfectious causes of SIRS include, but are not limited to, acute mesenteric ischemia, adrenal insufficiency, autoimmune disorders, burns, chemical aspiration, cirrhosis, cutaneous vasculitis, dehydration, drug reaction, electrical injuries, erythema multiforme, hemorrhagic shock, hematologic malignancy, intestinal perforation, medication side effect, for example, from theophylline, myocardial infarction, pancreatitis, seizure, substance abuse, stimulants, such as cocaine and amphetamines, surgical procedures, toxic epidermal necrolysis, transfusion reactions, upper gastrointestinal bleeding and vasculitis.
The sex-based mortality risk of severe SIRS is unknown. Females tend to have less inflammation from the same degree of pro-inflammatory stimuli because of the mitigating aspects of estrogen. The mortality rate among women with severe sepsis is similar to that of men who are 10 years younger; however, whether this protective effect applies to women with noninfectious SIRS is unknown. Prognosis depends on the etiologic source of SIRS, as well as on associated comorbidities. The mortality rates may vary depending on the causes of SIRS, any complications of organ failure that may occur, and the length of the hospital stay.
Systemic inflammatory response syndrome (SIRS) is a very common disease, although not all patients with SIRS require hospitalization or have diseases that progress to serious illness, since SIRS criteria are nonspecific and occur in patients who present a variety of conditions. Therefore, it is important to determine the severity of SIRS. To date, no reliable method has been developed that reliably predict the severity of SIRS. The present invention overcomes the deficiencies of the prior art, by providing reliable methods for predicting the severity of systemic inflammatory response syndrome (SIRS), diseases caused by neutrophil activation and/or inflammatory diseases accompanied by neutrophil activation in a subject in need thereof.